Mechanism of a transcriptional cross talk between transforming growth factor-β-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4

被引:44
作者
Chou, WC
Prokova, V
Shiraishi, K
Valcourt, U
Moustakas, A
Hadzopoulou-Cladaras, M
Zannis, VI
Kardassis, D [1 ]
机构
[1] Univ Crete, Sch Med, Dept Basic Sci, GR-71110 Iraklion, Greece
[2] Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, GR-71110 Iraklion, Greece
[3] Ludwig Inst Canc Res, S-75124 Uppsala, Sweden
[4] Aristotle Univ Thessaloniki, Dept Biol, Sect Genet Dev & Mol Biol, GR-54124 Thessaloniki, Greece
关键词
D O I
10.1091/mbc.E02-07-0375
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
We have shown previously that the transforming growth factor-P (TGFbeta)-regulated Sma-Mad (Smad) protein 3 and Smad4 proteins transactivate the apolipoprotein C-M promoter in hepatic cells via a hormone response element that binds the nuclear receptor hepatocyte nuclear factor 4 (HNF-4). In the present study, we show that Smad3 and Smad4 but not Smad2 physically interact with HNF4 via their Mad homology I domains both in vitro and in vivo. The synergistic transactivation of target promoters by Smads and HNF4 was shown to depend on the specific promoter context and did not require an intact beta-hairpin/ DNA binding domain of the Smads. Using glutathione S-transferase interaction assays, we established that two regions of HNF4, the N-terminal. activation function 1 (AF-1) domain (aa 1-24) and the C-terminal F domain (aa 388-455) can mediate physical Smad3/HNF-4 interactions in vitro. In vivo, Smad3 and Smad4 proteins enhanced the transactivation function of various GAL4-HNF-4 fusion proteins via the AF-1 and the adjacent DNA binding domain, whereas a single tyrosine to alanine substitution in AF-1 abolished coactivation by Smads. The findings suggest that the transcriptional cross talk between the TGFbeta-regulated Smads and HNF4 is mediated by specific functional domains in the two types of transcription factors. Furthermore, the specificity of this interaction for certain target promoters may play an important role in various hepatocyte functions, which are regulated by TGFbeta and the Smads.
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页码:1279 / 1294
页数:16
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